Loss of ALS2/Alsin Exacerbates Motor Dysfunction in a SOD1H46R-Expressing Mouse ALS Model by Disturbing Endolysosomal Trafficking

Hadano, Shinji; Otomo, Asako; Kunita, Ryota; Suzuki-Utsunomiya, Kyoko; Akatsuka, Akira; Koike, Masato; Akiyama, Masashi; Uchiyama, Yasuo; Itoyama, Yasuto; Ikeda, Joh E.

doi:10.1371/journal.pone.0009805

Cited by 100 publications

(92 citation statements)

References 62 publications

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“…Interestingly, blocking apoptosis also induced autophagy, a process implicated in the clearance of intracellular protein aggregates in several neurodegenerative diseases (41,42). Mounting evidence supports the notion that autophagy plays a largely protective role in neurodegeneration (43)(44)(45)(46). Indeed, a recent study reports that p62 interacts with mutant SOD1, suggesting a potential role for autophagy in the degradation of misfolded SOD1 species (47).…”

Section: Discussionmentioning

confidence: 94%

Blocking the mitochondrial apoptotic pathway preserves motor neuron viability and function in a mouse model of amyotrophic lateral sclerosis

Reyes

Fisher²,

Austgen³

et al. 2010

J. Clin. Invest.

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Apoptosis of motor neurons is a well-documented feature in amyotrophic lateral sclerosis (ALS) and related motor neuron diseases (MNDs). However, the role of apoptosis in the pathogenesis of these diseases remains unresolved. One possibility is that the affected motor neurons only succumb to apoptosis once they have exhausted functional capacity. If true, blocking apoptosis should confer no therapeutic benefit. To directly investigate this idea, we tested whether tissue-specific deletion in the mouse CNS of BCL2-associated X protein (BAX) and BCL2-homologous antagonist/killer (BAK), 2 proapoptotic BCL-2 family proteins that together represent an essential gateway to the mitochondrial apoptotic pathway, would protect against motor neuron degeneration. We found that neuronal deletion of Bax and Bak in a mouse model of familial ALS not only halted neuronal loss, but prevented axonal degeneration, symptom onset, weight loss, and paralysis and extended survival. These results show that motor neurons damaged in ALS activate the mitochondrial apoptotic pathway early in the disease process and that apoptotic signaling directly contributes to neuromuscular degeneration and neuronal dysfunction. Hence, inhibiting apoptosis upstream of mitochondrial permeabilization represents a possible therapeutic strategy for preserving functional motor neurons in ALS and other MNDs.

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Section: Discussionmentioning

confidence: 94%

Blocking the mitochondrial apoptotic pathway preserves motor neuron viability and function in a mouse model of amyotrophic lateral sclerosis

Reyes

Fisher²,

Austgen³

et al. 2010

J. Clin. Invest.

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show abstract

“…By contrast, the ALS-associated protein ALS2 (also known as alsin) regulates endolysosomal trafficking, potentially by mediating the fusion between endosomes and autophagosomes (Hadano et al, 2010), and another ALS-associated protein, VCP, also regulates autophagosome maturation (Ju et al, 2009;Tresse et al, 2010). Furthermore, ALS-associated mutations in the protein CHMP2B disrupt autophagosome maturation by inhibiting the fusion of autophagosomes with multivesicular bodies (Cox et al, 2010;Filimonenko et al, 2007;Lee et al, 2007).…”

Section: Autophagosome Maturation and Lysosomal Fusion In Diseasementioning

confidence: 99%

Autophagosome dynamics in neurodegeneration at a glance

Wong

Holzbaur

2015

Journal of Cell Science

115

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Autophagy is an essential homeostatic process for degrading cellular cargo. Aging organelles and protein aggregates are degraded by the autophagosome-lysosome pathway, which is particularly crucial in neurons. There is increasing evidence implicating defective autophagy in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Parkinson's disease and Huntington's disease. Recent work using live-cell imaging has identified autophagy as a predominantly polarized process in neuronal axons; autophagosomes preferentially form at the axon tip and undergo retrograde transport back towards the cell body. Autophagosomes engulf cargo including damaged mitochondria (mitophagy) and protein aggregates, and subsequently fuse with lysosomes during axonal transport to effectively degrade their internalized cargo. In this Cell Science at a Glance article and the accompanying poster, we review recent progress on the dynamics of the autophagy pathway in neurons and highlight the defects observed at each step of this pathway during neurodegeneration.

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“…6,7 Loss of alsin function, caused by a FALSlinked mutation, leads to the abnormal endolysosomal trafficking and contributes to motor neuron death. 8 We have independently shown that wild-type alsin suppresses mutant SOD1-induced neuronal cell death by activating a prosurvival pathway involving Rac1, PI3K and Akt3, and that FALS-linked mutations in the gene abolish the alsin function. 9,10 To further characterize the Akt-mediated prosurvival pathways that are linked to the ALS pathogenesis, we previously performed an yeast-two hybrid analysis and identified BTBD10 as an Akt3-binding protein.…”

mentioning

confidence: 99%

Reduced expression of BTBD10, an Akt activator, leads to motor neuron death

et al. 2012

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BTBD10, an Akt interactor, activates Akt by decreasing the protein phosphatase 2A-mediated dephosphorylation and inactivation of Akt. Overexpression of BTBD10 suppresses motor neuron death that is induced by a familial amyotrophic lateral sclerosis (ALS)-linked superoxide dismutase 1 (SOD1) mutant, G93A-SOD1 in vitro. In this study, we further investigated the BTBD10-mediated suppression of motor neuron death. We found that the small interfering RNA-mediated inhibition of BTBD10 expression led to the death of cultured motor neurons. In Caenorhabditis elegans (C. elegans), disruption of the btbd-10 gene caused not only loss of neurons, including both motor and touch-receptor neurons, but also a locomotion defect. In addition, we found that the expression of BTBD10 was generally decreased in the motor neurons from patients of sporadic ALS and transgenic mice overexpressing G93A-SOD1 (G93A-SOD1-transgenic mice). Collectively, these results suggest that the reduced expression of BTBD10 leads to motor neuron death both in vitro and in vivo. A gain-of-toxic-function of an intracellular molecule or a loss of normal function of an essential intracellular molecule, including an intracellular prosurvival signal, contributes to cell death. The Akt family of proteins (Akt1, 2 and 3 in mammalian cells) provides a major intracellular prosurvival signal by phosphorylating many target proteins. 1 The major upstream activator of Akt is the phosphatidylinositol 3-kinase (PI3K)-mediated signal that activates Akt by phosphorylation. Akt's activity is also regulated by protein phosphatase-mediated dephosphorylation. 2 In our previous study, we showed that BTBD10 activates Akt by inhibiting protein phosphatase 2A (PP2A)-mediated Akt dephosphorylation. 3 Recent advances in genetics and neuroscience have suggested that both gains of toxic and/or losses of normal function of intracellular molecules contribute to the pathogenesis of neurodegenerative diseases. Amyotrophic lateral sclerosis (ALS) is a representative motor neuron-specific neurodegenerative disease. 4 Approximately 10% of ALS cases are genetically inherited. 4,5 Dominant mutations in the superoxide dismutase 1 (SOD1) gene (the first identified familial ALS (FALS)-linked gene) account for approximately 20% of FALS cases. The gain-of-toxic-function of SOD1, caused by a FALS-linked mutation, is thought to be closely linked to the ALS pathogenesis. The second identified FALS-linked gene, a FALS-linked mutation of which results in an autosomal-recessive phenotype, encodes a protein named alsin. 6,7 Loss of alsin function, caused by a FALSlinked mutation, leads to the abnormal endolysosomal trafficking and contributes to motor neuron death. 8 We have independently shown that wild-type alsin suppresses mutant SOD1-induced neuronal cell death by activating a prosurvival pathway involving Rac1, PI3K and Akt3, and that FALS-linked mutations in the gene abolish the alsin function. 9,10 To further characterize the Akt-mediated prosurvival pathways that are linked to the ALS pathogenesi...

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Loss of ALS2/Alsin Exacerbates Motor Dysfunction in a SOD1H46R-Expressing Mouse ALS Model by Disturbing Endolysosomal Trafficking

Cited by 100 publications

References 62 publications

Blocking the mitochondrial apoptotic pathway preserves motor neuron viability and function in a mouse model of amyotrophic lateral sclerosis

Blocking the mitochondrial apoptotic pathway preserves motor neuron viability and function in a mouse model of amyotrophic lateral sclerosis

Autophagosome dynamics in neurodegeneration at a glance

Reduced expression of BTBD10, an Akt activator, leads to motor neuron death

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